DP1 Receptor Blockade Attenuates Microglial Senescence and Cognitive Decline Caused by PTGDS in Exosomes From Aged Brains

ABSTRACT Aging leads to neurodegenerative diseases, such as cognitive decline, which are induced by persistent chronic low‐grade inflammation in the brain driven by microglial activation. However, whether and how brain‐derived exosomes from aged mice (A‐exo) induce a pro‐inflammatory state and cellular senescence in microglia within the aging brain is poorly understood. Here, we report that brain‐derived exosomes from aged mice (A‐exo) cause cognitive decline in normal young mice, inducing microglial overactivation, lipid droplet accumulation, and senescence‐associated secretory phenotype (SASP) secretion. This abnormal microglial activity arises from the elevated expression of PTGDS in A‐exo due to mouse aging, resulting in increased central and peripheral D‐prostanoid receptor 1 (DP1) ligand PGD2 levels, which subsequently leads to sustained DP1 signaling activation. Consequently, this process promotes myeloid cell infiltration, cellular senescence, and cognitive decline by generating a senescent, pro‐inflammatory microglial phenotype. Blocking the DP1 receptor ameliorates A‐exo‐mediated microglial overactivation, myeloid cell infiltration, and cellular senescence. Strikingly, DP1 receptor blockade improves cellular senescence, neuroinflammation, and cognitive decline in aged mice. Our findings reveal a systemic mechanism underlying the sustained activation of microglia following brain aging, paving the way for improving chronic neuroinflammation, cellular senescence, and cognitive decline associated with aging.